Pharmaceutical formulations used for treating the eyes, ears or nose typically require preservation to prevent their contamination with potentially harmful microorganisms. For this purpose specially selected antimicrobial agents are added to the formulations as preservatives. The antimicrobial agents used are normally expected to exhibit sufficient biocidal activity so as to preclude the harboring of microorganisms. Similarly, formulations used for the care, cleaning and disinfection of contact lenses must be able to exert antimicrobial activity against those microorganisms likely to contaminate such lenses. A number of small organic molecules have been used as preservatives and disinfectants in ophthalmic lens care formulations, for example, compounds such as benzalkonium chloride (BAC), chlorhexidine, and thimerosal.
Benzalkonium choroide (BAK, BAC) is a member of a class of compounds known as quaternary ammonium compounds, Quats or QACs. This class also includes compounds such as cetyl trimethylammonium bromide (CTMB), cetylpyridinium chloride (Cetrim), cetylpyridinium chloride (CPC) and benzethonium chloride (BZT). Benzalkonium chloride is a mixture of alkylbenzyl dimethylammonium chlorides of various alkyl chain lengths. The greatest bactericidal activity is associated with the C12-C14 alkyl derivatives. Benzalkonium chloride has been used commercially as a disinfectant and spemicide in a wide variety of products, for example, hand and face washes, mouthwashes, spermicidal creams, to name just a few, as well as in various formulations useful for treating the eye or nose.
While potent in regard to antimicrobial activity, practitioners have become aware over the years of the potential for some of these small organic antimicrobial agents to be toxic to sensitive tissues, for example, to the cornea of the eye. In addition, some of these small molecules have been found to accumulate in contact lenses, particularly in soft, hydrophilic contact lenses. As these compounds may leach from the lenses while they are worn in the eye, the sensitive tissues of the eye may be repeatedly exposed to these agents which can cause additional irritation and possible damage and irritation to the cornea.
For their potential in overcoming some of the disadvantages of the smaller organic, monomeric compounds described above, polymeric quaternary ammonium compounds have been investigated for a number of years.
For example, British Patent No. 536,017 (Aug. 30, 1941), assigned to E. I. DuPont de Nemours (the “DuPont Patent”), discloses linear polymeric quaternary ammonium compounds and methods for their preparation. The compounds of the DuPont Patent were envisioned to be useful in photographic processing, to treat leather, as mold inhibitors and pesticides, and as modifying agents. There is, however, no mention of use of these compounds as disinfectants or preservatives in pharmaceutical products.
U.S. Pat. Nos. 3,931,319 (Jan. 6, 1976), 4,001,432 (Jan. 4, 1977) and 4,012,446 (Mar. 15, 1977), all issued to Green, et al., disclose a group of high molecular weight “capped” linear polymeric quaternary ammonium compounds found to be effective microbiocides (antimicrobials). The Green, et al. compounds are “capped” in the sense that both ends of the chains terminate in quaternary ammonium moieties. In a continuation-in-part application, now U.S. Pat. No. 4,027,020 (May 31, 1977), Green, et al. disclose a process for making randomly capped linear polymeric quaternary ammonium compounds; that is, the polymers produced by the improved process include those with very short chain lengths as well as those having relatively long chain lengths. These compounds were also found to have antimicrobial activity.
U.S. Pat. Nos. 4,407,791 (Oct. 4, 1983) and 4,525,346 (Jun. 25, 1985), both issued to Stark, disclose disinfecting solutions for contact lenses, wherein the aqueous solutions contain the Green, et al. polymers, including the compound polyquaternium-1, commercially known as Onamer M® or PolyQuad®.
Practitioners involved with developing formulations for use in lens care or ophthalmic compositions for ocular use recognize that there are many trade-offs and choices to be made in developing a particular formulation. In the case of biocidal compounds, for example, it is often found that the more potent biocide is also more toxic to sensitive ocular tissues. Certain agents may also show differential selectivity in activity, is for example, showing a greater or lower level of antibacterial activity against particular microorganisms, or class of microorganisms, e.g., Gram-positive or Gram-negative bacteria, or fungi, e.g., C. Albicans. While in some applications a broad spectrum of activity is desirable, in others a selective activity may be preferred, for example, where the practitioner desires to boost the activity of an existing formulation against a particular microorganisms or class or microorganism.
When optimizing a particular formulation, in addition to demonstrating biocidal activity against a suitable range of microorganisms, there are also several additional factors to consider; for example, mutual compatibility of formulation constituents, relative availability and/or raw material cost, and, in the case of lens care formulations, contact lens uptake, and so on. More recently, increasing concern for the implications of biocide accumulation in the environment, and also the phenomena of antimicrobial resistance are among the new factors to consider when selecting a particular preserving agent.
Considering these challenges, a preservative and/or disinfection agent which has effective antimicrobial activity, preferably across a range of microorganisms, and which also is not toxic and/or damaging to the cornea or other mucosal tissues, does not cause irritation to the sensitive tissues of the eye, ear or nose, and is also comfortable to use would be highly desirable. In addition, a preservative which is compatible with the articles of its intended use as well as with other formulation components would be likewise desirable. Finally, a preservative which is readily degraded into nontoxic and biologically inactive products after its intended purpose has been achieved in vivo, as well as in the environment, would likewise be considered highly advantageous. The present invention is directed to satisfying one or more of these needs.